This study aimed to determine possible association of eight polymorphisms of seven MMP genes with essential hypertension (EH) in a Caucasian population of Central Russia. Eight SNPs of the MMP1, ...MMP2, MMP3, MMP7, MMP8, MMP9, and MMP12 genes and their gene-gene (epistatic) interactions were analyzed for association with EH in a cohort of 939 patients and 466 controls using logistic regression and assuming additive, recessive, and dominant genetic models. The functional significance of the polymorphisms associated with EH and 114 variants linked to them (r
≥ 0.8) was analyzed in silico. Allele G of rs11568818 MMP7 was associated with EH according to all three genetic models (OR = 0.58-0.70, p
= 0.01-0.03). The above eight SNPs were associated with the disorder within 12 most significant epistatic models (OR = 1.49-1.93, p
< 0.02). Loci rs1320632 MMP8 and rs11568818 MMP7 contributed to the largest number of the models (12 and 10, respectively). The EH-associated loci and 114 SNPs linked to them had non-synonymous, regulatory, and eQTL significance for 15 genes, which contributed to the pathways related to metalloendopeptidase activity, collagen degradation, and extracellular matrix disassembly. In summary, eight studied SNPs of MMPs genes were associated with EH in the Caucasian population of Central Russia.
Abstract
This study analyzed the association of functionally significant SNPs of matrix metalloproteinase (
MMP
) genes in the development of peptic ulcer disease (PUD) in Caucasians from Central ...Russia. Ten SNPs of the
MMP-1, MMP-2, MMP-3, MMP-8
, and
MMP-9
genes were analyzed for association with PUD in a cohort of 798 patients with PUD (including 404
H. pylori
-positive and 394
H. pylori
-negative) and 347
H. pylori
-negative controls using logistic regression and assuming the additive, recessive, and dominant genetic models. The variants of
MMP-1
,
MMP-2
,
MMP-3
, and
MMP-8
did not manifest any significant associations with the diseases. Five SNPs of the
MMP-9
gene demonstrated such association. Allele G of the rs17576
MMP-9
locus conferred a higher risk for PUD (OR
adj
= 1.31, p
perm
= 0.016), haplotype AACG of loci rs17576-rs3787268-rs2250889-rs17577 of the
MMP-9
gene decreased risk for PUD (OR
adj
= 0.17, p
perm
= 0.003). Also, allele C of rs3918249, allele G of rs17576 and haplotype CG of rs3918249-rs17576 of the
MMP-9
gene increased risk for
H. pylori
-positive PUD (OR
adj
= 1.82, p
perm
= 0.002; OR
adj
= 1.53–1.95 p
perm
= 0.001–0.013 and OR
adj
= 1.49 p
perm
= 0.009 respectively). The above loci and 50 linked to them possess significant regulatory effects and may affect the alternative splicing of four genes and the expression of 17 genes in various organs and tissues related to the PUD pathogenesis.
Background and purpose The study analyzed the association of functionally significant polymorphisms of matrix metalloproteinases (MMPs) genes with the development of gastric ulcer (GU) in Caucasians ...from Central Russia. Methods The 781 participants, including 434 patients with GU (196 Helicobacter pylori (H. pylori)-positive and 238 H. pylori-negative) and 347 controls (all H. pylori-negative) were recruited for the study. Ten SNPs of the MMP1 (rs1799750), MMP2 (rs243865), MMP3 (rs679620), MMP8 (rs1940475), and MMP9 (rs3918242, rs3918249, rs3787268, rs17576, rs17577, and rs2250889) genes were considered for association with GU using multiple logistic regression. The SNPs associated with GU and loci linked (r.sup.2 greater than or equal to0.8) to them were analyzed in silico for their functional assignments. Results The SNPs of the MMP9 gene were associated with H. pylori-positive GU: alleles C of rs3918249 (OR = 2.02, p.sub.perm = 0.008) and A of rs3787268 (OR = 1.60-1.82, p.sub.perm less than or equal to 0.016), and eight haplotypes of all studied MMP9 gene SNPs (OR = 1.85-2.04, p.sub.perm less than or equal to 0.016) increased risk for H. pylori-positive GU. None of the analyzed SNPs was independently associated with GU and H. pylori-negative GU. Two haplotypes of the MMP9 gene (contributed by rs3918242, rs3918249, rs17576, and rs3787268) increased risk for GU (OR = 1.62-1.65, p.sub.perm less than or equal to 0.006). Six loci of the MMP9 gene, which are associated with H. pylori-positive GU, and 65 SNPs linked to them manifest significant epigenetic effects, have pronounced eQTL (17 genes) and sQTL (6 genes) values. Conclusion SNPs of the MMP9 were associated with H. pylori-positive GU but not with H. pylori-negative GU in Caucasians of Central Russia.
This study aimed to analyze the gender-specific association of the filaggrin (FLG) gene polymorphisms with atopic dermatitis (AD) in Caucasians from the central region of Russia.
The study sample ...consisted of 906 female (including 474 patients with AD and 432 controls) and 406 male (such as 226 patients with AD and 180 controls) participants. Genotyping of ten polymorphisms of the FLG gene was done. The logistic regression was used to analyze the associations. A total of 125 SNPs (seven AD-associated SNPs and 118 proxy SNPs, r2≥0.8) FLG gene were used for the in silico functional annotation analysis in the females.
Significant associations were identified between seven SNPs of the FLG gene (rs12130219, rs61816761, rs558269137, rs12144049, rs3126085, rs471144, rs6661961) and AD in females: rs12144049 was associated independent individually (for allele C OR = 1.71, 95%Сl 1.19-2.46, рperm = 0.004 and OR = 1.76, 95%Сl 1.18-2.63, рperm = 0.006 according to the additive and dominant genetic models, respectively) and seven SNPs of the FLG gene within 14 haplotypes. Haplotype GGT rs61816761-rs3126085-rs12144049 showed the strongest association (OR = 0.55, рperm = 0.001). No association between the analyzed SNPs and AD was determined in the male group. The subsequent bioinformatic analysis predicted the SNPs of the FLG gene that possessed epigenetic and non-synonymous effects, were involved in the control of gene expression and alternative splicing of genes that contribute to AD pathophysiology.
Polymorphisms of the FLG gene are associated with AD in females but not in males in the Caucasian population of Central Russia.
We conducted this study to explore the association between matrix metalloproteinase (MMP) gene polymorphisms and breast cancer (BC) risk in the Caucasian women of Russia. In total, 358 affected (BC) ...and 746 unaffected (cancer-free) women were included in this case-control retrospective study. From BC-related genes in previous studies, ten single nucleotide polymorphisms (SNPs) in five MMP genes (MMP1, 2, 3, 8, 9) were genotyped. The BC risk was calculated by logistic regression (to evaluate the SNPs’ independent effects) and model-based multifactor dimensionality reduction (MB-MDR) (to identify SNP−SNP interactions) methods. The allelic variants’ distribution of c.836 A > G (rs17576) and c. 1721 C > G (rs2250889) MMP9 was significantly different between BC and cancer-free women: for G minor alleles, these SNPs manifested disorder protective effects (OR 0.82 and OR 0.67−0.71, respectively, pperm ≤ 0.035). Eleven haplotypes of six SNPs MMP9 were involved in BC risk (nine haplotypes) and protective (two haplotypes) effects. All 10 SNPs of the MMP genes examined were associated with BC within the 13 SNP−SNP interaction simulated models, with a pivotal role of the two-locus (rs17577 × rs3918242) MMP9 epistatic interaction (defined as 1.81% BC entropy within more than 60% of the genetic models). Under in silico bioinformatics, BC susceptibility MMP polymorphic loci are located in functionally active genome regions and impact genes expression and splicing “regulators” in the mammary gland. The biological pathways of BC MMP candidate genes are mainly realized due to metalloendopeptidase activity and extracellular matrix organization (structure, disassembly, metabolic process, etc.). In conclusion, our data show that MMP gene polymorphisms are related to BC susceptibility in the Caucasian women of Russia.
In our work, the associations of GWAS (genome-wide associative studies) impact for sex-hormone-binding globulin (SHBG)-level SNPs with the risk of breast cancer (BC) in the cohort of Caucasian women ...of Russia were assessed. The work was performed on a sample of 1498 women (358 BC patients and 1140 control (non BC) subjects). SHBG correlated in previously GWAS nine polymorphisms such as rs780093
, rs17496332
, rs3779195
, rs10454142
, rs7910927
, rs4149056
, rs440837
, rs12150660
, and rs8023580
have been genotyped. BC risk effects of allelic and non-allelic SHBG-linked gene SNPs interactions were detected by regression analysis. The risk genetic factor for BC developing is an SHBG-lowering allele variant C rs10454142
(additive genetic model OR = 1.31; 95%CI = 1.08-1.65; p
= 0.024; power = 85.26%), which determines 0.32% of the cancer variance. Eight of the nine studied SHBG-related SNPs have been involved in cancer susceptibility as part of nine different non-allelic gene interaction models, the greatest contribution to which is made by rs10454142
(included in all nine models, 100%) and four more SNPs-rs7910927
(five models, 55.56%), rs17496332
(four models, 44.44%), rs780093
(four models, 44.44%), and rs440837
(four models, 44.44%). For SHBG-related loci, pronounced functionality in the organism (including breast, liver, fibroblasts, etc.) was predicted in silico, having a direct relationship through many pathways with cancer pathophysiology. In conclusion, our results demonstrated the involvement of SHBG-correlated genes polymorphisms in BC risk in Caucasian women in Russia.
Age at menarche (AAM) is an important marker of the pubertal development and function of the hypothalamic-pituitary-ovarian system. It was reported as a possible factor for a risk of uterine ...leiomyoma (UL). However, while more than 350 loci for AAM have been determined by genome-wide association studies (GWASs) to date, no studies of these loci for their association with UL have been conducted so far. In this study, we analyzed 52 candidate loci for AAM for possible association with UL in a sample of 569 patients and 981 controls. The results of the study suggested that 23 out of the 52 studied polymorphisms had association with UL. Locus rs7759938
was individually associated with the disease according to the dominant model. Twenty loci were associated with UL within 11 most significant models of intergenic interactions. Nine loci involved in 16 most significant models of interactions between single-nucleotide polymorphism (SNP), induced abortions, and chronic endometritis were associated with UL. Among the 23 loci associated with UL, 16 manifested association also with either AAM (7 SNPs) or height and/or body mass index (BMI) (13 SNPs). The above 23 SNPs and 514 SNPs linked to them have non-synonymous, regulatory, and expression quantitative trait locus (eQTL) significance for 35 genes, which play roles in the pathways related to development of the female reproductive organs and hormone-mediated signaling false discovery rate (FDR) ≤ 0.05. This is the first study reporting associations of candidate genes for AAM with UL.
The present study was designed to examine whether sex hormone polymorphisms proven by GWAS are associated with endometriosis risk. Unrelated female participants totaling 1376 in number (395 ...endometriosis patients and 981 controls) were recruited into the study. Nine single-nucleotide polymorphisms (SNPs) which GWAS correlated with circulating levels of sex hormones were genotyped using a TaqMan allelic discrimination assay. FSH-lowering, and LH- and testosterone-heightening polymorphisms of the
promoter (allelic variants A rs11031002 and C rs11031005) exhibit a protective effect for endometriosis (OR = 0.60-0.68). By contrast, the TT haplotype loci that were GWAS correlated with higher FSH levels and lower LH and testosterone concentrations determined an increased risk for endometriosis (OR = 2.03). Endometriosis-involved epistatic interactions were found between eight loci of sex hormone genes (without rs148982377
) within twelve genetic simulation models. In silico examination established that 8 disorder-related loci and 80 proxy SNPs are genome variants affecting the expression, splicing, epigenetic and amino acid conformation of the 34 genes which enrich the organic anion transport and secondary carrier transporter pathways. In conclusion, the present study showed that sex hormone polymorphisms proven by GWAS are associated with endometriosis risk and involved in the molecular pathophysiology of the disease due to their functionality.
We aimed to explore the potential link of maternal age at menarche (mAAM) gene polymorphisms with risk of the fetal growth restriction (FGR). This case (FGR)-control (FGR free) study included 904 ...women (273 FGR and 631 control) in the third trimester of gestation examined/treated in the Departments of Obstetrics. For single nucleotide polymorphism (SNP) multiplex genotyping, 50 candidate loci of mAAM were chosen. The relationship of mAAM SNPs and FGR was appreciated by regression procedures (logistic/model-based multifactor dimensionality reduction MB-MDR) with subsequent in silico assessment of the assumed functionality pithy of FGR-related loci. Three mAAM-appertain loci were FGR-linked to genes such as
(rs7538038) (effect allele G-odds ratio (OR)
= 0.63/p
= 0.0003; OR
= 0.61/p
= 0.001; OR
= 0.56/p
= 0.001),
(rs999460) (effect allele A-OR
= 1.37/p
= 0.003; OR
= 1.45/p
= 0.002; OR
= 2.41/p
= 0.0002),
(rs12444979) (effect allele T-OR
= 1.67/p
= 0.0003; OR
= 1.59/p
= 0.011; OR
= 1.56/p
= 0.009). The haplotype ACA
gene (rs555621*rs11031010*rs1782507) was FRG-correlated (OR = 0.71/p
= 0.05). Ten FGR-implicated interworking models were founded for 13 SNPs (p
≤ 0.001). The rs999460
and rs12444979
interplays significantly influenced the FGR risk (these SNPs were present in 50% of models). FGR-related mAAM-appertain 15 polymorphic variants and 350 linked SNPs were functionally momentous in relation to 39 genes participating in the regulation of hormone levels, the ovulation cycle process, male gonad development and vitamin D metabolism. Thus, this study showed, for the first time, that the mAAM-appertain genes determine FGR risk.
The aim of the study was directed at studying the sex-specific features of the correlation between genome-wide association studies (GWAS)-noticeable polymorphisms and hypertension (HTN). In two ...groups of European subjects of Russia (
= 1405 in total), such as men (
= 821 in total:
= 564 HTN,
= 257 control) and women (
= 584 in total:
= 375 HTN,
= 209 control), the distribution of ten specially selected polymorphisms (they have confirmed associations of GWAS level with blood pressure (BP) parameters and/or HTN in Europeans) has been considered. The list of studied loci was as follows: (
) rs932764 A > G, (
) rs1173771 G > A, (
) rs7302981 G > A, (
) rs1799945 C > G, (
) rs4387287 C > A, (
) rs805303 G > A, (
) rs167479 T > G, (
) rs633185 C > G, (
) rs8068318 T > C, and (
) rs2681472 A > G. The contribution of individual loci and their inter-locus interactions to the HTN susceptibility with bioinformatic interpretation of associative links was evaluated separately in men's and women's cohorts. The men-women differences in involvement in the disease of the BP/HTN-associated GWAS SNPs were detected. Among women, the HTN risk has been associated with
rs1799945 C > G (genotype GG was risky; OR
= 11.15 p
= 0.014) and inter-locus interactions of all 10 examined SNPs as part of 26 intergenic interactions models. In men, the polymorphism
rs805303 G > A (genotype AA was protective; OR
= 0.30 p
= 0.0008) and inter-SNPs interactions of eight loci in only seven models have been founded as HTN-correlated. HTN-linked loci and strongly linked SNPs were characterized by pronounced polyvector functionality in both men and women, but at the same time, signaling pathways of HTN-linked genes/SNPs in women and men were similar and were represented mainly by immune mechanisms. As a result, the present study has demonstrated a more pronounced contribution of BP/HTN-associated GWAS SNPs to the HTN susceptibility (due to weightier intergenic interactions) in European women than in men.
PDF
